The capacity to assay hematopoietic progenitor and stem cells in humans and mice, and factors which regulate the growth of these cells, allows us to investigate normal and abnormal hematopoiesis in vitro and in vivo. We believe that negative feedback mechanisms play a role in the physiological regulation of stem and progenitor cells and are important in the development and progression of acute and chronic leukemia, myeloproliferative and myelodysplastic disorders. We are using in vitro and in vivo approaches to study a cell-free inhibitory activity, leukemiaassociated inhibitory activity (LIA), which we have identified as acidic isoferritins (AIF). AIF are well-characterized iron-binding glycoproteins which we have available in purified form. The extremely low concentrations needed for action in vitro and its derivation from normal Ia-antigenpositive monocytes suggest that it may be physiologically relevant. The increase of acidic isoferritins during leukemia from Ia-antigen-negative non-T, non-B cells with Fc receptors, its suppressive action on normal granulocyte-macrophage, erythroid and multipotential progenitor cells from patients with leukemia, (who are HLA-DR(Ia)-antigen negative) suggest it may be involved in the pathogenesis and progression of leukemia and other blood disorders. AIF has been found in normal mouse bone marrow cells during continuous marrow cultures in vitro, and the release of AIF from human monocytes is restricted genetically by HLA-DR (Ia)-antigens at the level of T lymphocyte-monocyte interactions. We will define further the mechanisms of production and action of acidic isoferritin-inhibitory activity in vitro. Normal and leukemic mice will be used to determine action in vivo, and the significance of acidic isoferritins to disease progression. We will explore means to modulate the production and action of acidic isoferritins in vitro and in vivo, and will determine if they may be used as a supplement to chemotherapy treatment protocols.